PAIN MECHANISMS CORE (PMC) The University of Michigan Fibromyalgia (FM) CORT proposes that presence of centralized pain will render individuals less responsive to analgesic therapies aimed at peripheral/nociceptive pain (surgery, biologics, opioids) and that this centralized pain phenotype has stereotypical clinical and neurobiological features similar to FM even when it is co-morbid with other musculoskeletal pain conditions with disparate underlying pain mechanisms. The PMC will use quantitative sensory testing (QST) and neuroimaging methods to characterize the degree of centralization in three cohorts of musculoskeletal pain patients: osteoarthritis of the hip, rheumatoid arthritis, and carpal tunnel syndrome. We will collect these same measures in individuals with FM and heathy controls, which will enable us to demonstrate that these neurobiological measures are increasingly abnormal in the transition from low (healthy controls) to high degrees of fibromyalgia (FM cohort). The Specific Aims of the CORT supported by the PMC are as follows: 1) To demonstrate that individuals with the highest FM Survey Criteria scores will have similar neurobiological findings of pain centralization, including abnormal QST findings and aberrant findings on functional, chemical and structural neuroimaging. We hypothesize that in all three musculoskeletal pain cohorts, the individuals with greater degrees of pain centralization (i.e. highest scores on the FM Survey Criteria) will demonstrate a) more hyperalgesia and decreased pain inhibition on QST and functional magnetic resonance imaging (fMRI), b) characteristic functional connectivity changes on fMRI (e.g., decreased functional connectivity to descending antinociceptive brain networks and increased connectivity to pronociceptive regions), c) increased CNS levels of excitatory neurotransmitters in pronociceptive regions on proton spectroscopy (i.e., glutamate in posterior insula), and d) increases in primary somatosensory/motor cortex volume. 2) To identify the clinical and mechanistic features of two important subsets of centralized pain: top-down activity independent centralization (i.e. previously termed primary FM) vs. bottom-up activity-dependent pain centralization or central sensitization (i.e. previously termed secondary FM) by exploring changes in QST/MRI measures in OA and carpel tunnel patients 6 months following surgery. It is critically important to better understand these mechanistic phenotypes of centralization since one group will benefit more from aggressive analgesic therapy aimed at the periphery.